(Genome-wide Association Studies) GWAS have identified ∼42 late-onset Alzheimer’s disease (LOAD)-associated loci, each of which contains multiple single nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) and most of these SNPs are in the non-coding region of human genome. However, how these SNPs regulate risk gene expression remains unknown. In this work, by using a set of novel techniques, we identified 6 functional SNPs (fSNPs) rs9271198, rs9271200, rs9281945, rs9271243, and rs9271247 on the LOAD-associated HLA-DRB1/DQA1 locus and 42 proteins specifically binding to five of these 6 fSNPs. As a proof of evidence, we verified the allele-specific binding of GATA2 and GATA3, ELAVL1 and HNRNPA0, ILF2 and ILF3, NFIB and NFIC, as well as CUX1 to these five fSNPs, respectively. Moreover, we demonstrate that all these nine proteins regulate the expression of both HLA-DQA1 and HLA-DRB1 in human microglial cells. The contribution of HLA class II to the susceptibility of LOAD is discussed.

（全基因组关联研究）GWAS 已鉴定出约 42 个迟发性阿尔茨海默氏病 (LOAD) 相关位点，每个位点均包含连锁不平衡 (LD) 中的多个单核苷酸多态性 (SNP)，并且大多数这些 SNP 均处于非连锁不平衡状态。 -人类基因组的编码区。然而，这些 SNP 如何调节风险基因表达仍然未知。在这项工作中，通过使用一组新技术，我们在 LOAD 相关的HLA-DRB1/DQA1位点上鉴定了 6 个功能性 SNP (fSNP) rs9271198、rs9271200、rs9281945、rs9271243 和 rs9271247，以及与其中 5 个特异性结合的 42 个蛋白质。 6 个 fSNP。作为证据证明，我们验证了 GATA2 和 GATA3、ELAVL1 和 HNRNPA0、ILF2 和 ILF3、NFIB 和 NFIC 以及 CUX1 分别与这五个 fSNP 的等位基因特异性结合。此外，我们证明所有这九种蛋白均可调节人小胶质细胞中HLA-DQA1和HLA-DRB1的表达。讨论了 HLA II 类对 LOAD 敏感性的贡献。